In this application we are using multidisciplinary approaches to investigate the common molecular mechanisms by which lipoprotein receptors of the low-density lipoprotein (LDL) receptor gene family regulate on one hand the integrity of the vascular wall, and on the other control development and function of the brain in the embryo as well as in the adult. During the first funding period we showed that the very-low-density lipoprotein receptor (VLDLR) and the Apolipoprotein E receptor-2 (ApoER2) function not only as transporters for cholesterol and other lipids, but also as developmentally essential signaling receptors that convey an important positional cue to migrating neurons that controls the formation of the neocortex, the hippocampus and the cerebellum. We showed that transmission of this signal involves the activation of a series of intracellular kinases. We also demonstrated that the same pathway remains active in the adult brain, where it no longer controls cell migration, but instead participates directly in neurotransmission, learning and memory. This novel role in the mature nervous system is of particular and immediate biomedical importance, since ApoE, a cholesterol transport molecule that binds to this class of lipoprotein receptors and can interfere with their signaling functions, is genetically strongly associated with Alzheimer's disease (AD). One focus during the next funding period thus will be the conceptual implications for the molecular pathogenesis of AD as well as atherosclerosis that arise from these findings. Specifically, we will investigate how VLDLR and ApoER2 interact with ApoE, signaling molecules and neurotransmitter receptors in the synapses of neurons in the adult brain and in the vascular wall, and how lipoprotein receptors integrate such diverse functions in vivo. This may provide novel targets for rational drug design and treatment of atherosclerosis as well as of AD, both disorders of increasing medical and socio-economic importance.